The intravenous (IV) route is commonly used in adults for induction of anesthesia. It is rapid, comfortable, pleasant and predictable. With the availability of EMLA (eutectic mixture of local anesthetic) the IV route is becoming popular in children as well. IV agents like propofol can also be used to maintain anesthesia.
Thiopentone, the first clinically useful intravenous anesthetic, was first used in clinical practice in 1934. This marked the beginning of modern anesthesia and use of the intravenous route for induction of anesthesia. Inhalational agents were generally used for maintenance.
The properties of an ideal intravenous anesthetic agent's are:
- Should produce rapid, smooth induction within one arm-brain circulation time (< 30 seconds)
- Should preferably have analgesic properties
- Should not produce pain on injection; should be possible to use intramuscularly if needed
- Should not be epileptogenic or raise intracranial pressure
- Should not cause myocardial depression or irritability
- Should not cumulate on infusion
- Metabolism should be independent of renal/hepatic function; metabolites should be inactive and non-toxic
- Should be non-teratogenic.
Although no currently used agent fulfils all these criteria, they are useful yardsticks to assess new agents.
This chapter will discuss thiopentone, ketamine and propofol which are the most widely used intravenous anesthetic agents, in detail. Passing reference will be made to other agents mainly to highlight the advantages these three have over the others. The second part of this chapter will deal with the commonly used opioids in the perioperative period.4
Barbiturates
Different barbiturates were used as sedatives in the 1920s. Since their actions were unpredictable, research was carried out making substitutions on the barbiturate ring (Fig. 1.2a) leading to compounds with known and/or desirable properties. Of these, sodium thiopentone emerged as the compound with the most acceptable properties. Table 1.1 summarises the effect of substitution.
It is a yellow colored powder with a faint garliclike smell, available in vials containing 500 mg or 1g. The vial contains six parts of sodium carbonate to 100 parts of barbiturate (by weight) in an atmosphere of nitrogen. Sodium carbonate produces free hydroxyl ions in solution, and is added to prevent the precipitation of insoluble free acid by atmospheric CO2. Thiopentone is dissolved in saline/distilled water to make a 25 mg/ml solution. This is a racemic mixture containing two stereoisomers and has a pH of 10.5-10.8. The solution remains stable in room temperature for up to two weeks, but should be discarded earlier if it appears cloudy. Because of strong alkalinity the solution is bacteriostatic, and also physically incompatible with acidic drugs normally administered as sulphates, chlorides or hydrochlorides.
Actions on the Central Nervous System
Thiopentone produces anesthesia in less than 30 seconds after IV administration. This is due to (i) high vascularity of the brain and (ii) the high lipid solubility of thiopentone. It is a poor analgesic; in fact it has an ‘antanalgesic’ effect, due to which a patient with a painful condition may have an increased perception of pain and may become very restless in the recovery period.
It reduces intracranial pressure (ICP) due to cerebral vasoconstriction which leads to a reduction in cerebral blood flow (CBF). Cerebral metabolic rate (CMRO2) is also reduced. Both these properties have made thiopentone the anesthetic agent of choice in patients with elevated ICP (head injury, intracranial tumor) and as an agent for cerebral protection (‘barbiturate coma’). It is a potent anticonvulsant. Consciousness is regained in 5-10 minutes after a single IV dose.
Actions on the Cardiovascular System
Mean arterial blood pressure falls with administration of thiopentone due to a dose-dependent reduction in vascular tone and some myocardial depression especially with high doses. These effects are of concern in all patients with low, fixed cardiac output states. This group includes hypovolemic patients (traumatic shock), patients with valvular stenoses (mitral, aortic), patients on vasodilators or beta-blockers and patients with ischemic heart disease, constrictive pericarditis or cardiac tamponade. Hypotension can be profound, refractory to treatment and can result in mortality. In fact, thiopentone had fallen out of favor in 1934 shortly after its introduction owing to the large number of war casualties resulting after its use on soldiers with hypovolemic shock in World War II. It was then known as the ideal agent for euthanasia’.
Effects on the Respiratory System
There is often a deep breath or yawn followed by a brief period of apnea. Ventilatory drive is reduced, leading to a fall in both the respiratory rate and tidal volume. Bronchial muscle tone increases and occasionally bronchospasm is induced. Laryngospasm may be induced if food or secretions enter the larynx, or by surgical stimulation under light anesthesia.
MISCELLANEOUS EFFECTS
Intraocular pressure is reduced. Conjunctival, corneal, and eyelash reflexes are abolished. Abolition of the eyelash reflex is used as a sign of completion of anesthetic induction. Skeletal muscle tone is reduced in high doses; however this is inadequate for surgical purposes. In normal doses it has little effect on the uterine muscle. Although it crosses the placenta, the fetal drug concentration is lower than the maternal blood levels. Both hepatic and renal function are transiently depressed. Thiopentone may induce various cytochrome P-450 isoenzymes; in chronic liver disease the effects are prolonged with delayed recovery.
Pharmacokinetics
Blood concentration drops rapidly after intravenous injection. 75-85% drug is albumin bound. In malnutrition, chronic renal failure and other conditions with hypoalbuminemia, less drug is protein-bound, hence more free drug is available. Action of the drug is dependent on the free plasma concentration of drug.
Thiopentone rapidly diffuses into the CNS because of its lipid solubility and high un-ionised fraction. Consciousness returns when the brain concentration falls as a result of re-distribution in the body. At this time nearly all the drug is still present in the body.
Thiopentone is predominantly metabolised in the liver. Metabolism is a linear process when single doses are concerned (10-15% of the remaining drug is metabolised each hour). Hence up to 30% of drug is still in the body after 4-6 hours. The metabolites are thiopental carboxylic acid (inactive), hydroxythiopental (inactive) and pentobarbital (active, with half-life of 20-50 hours). This leads to a hangover effect. With thiopentone infusions the metabolism follows non-linear, or zero-order kinetics and significant amounts are present in the plasma, leading to time prolonged recovery.
Dosage and Administration
Thiopentone is administered as a 2.5% (25 mg/ml) solution intravenously. 1-2 ml should be injected initially to check that the patient does not have pain at the site of 6injection. The dose in healthy adults is 4-5 mg/kg administered over 15 seconds. Consciousness will be lost in 30 seconds; if the eyelash reflex is not lost then a further 50-100 mg should be given. Children require about 6 mg/kg, and elderly patients 2.5-3 mg/kg. In patients where the cardiovascular system is depressed (e.g. as in hypovolemic shock) as little as 50 mg may be required.
Adverse Effects and Problems with Thiopentone
- Hypotension: This is more likely to happen if excessive doses are given or if a ‘normal’ dose is given to a hypovolemic patient or one with a low fixed cardiac output. Risk of hypotension is reduced if the drug is injected slowly. Thiopentone should not be injected in the sitting position.
- Respiratory depression: The risk is increased if opioids have also been administered. Thiopentone should be injected only where facilities for artificial ventilation are available.
- Tissue necrosis: Perivenous injection may lead to local tissue necrosis. If perivenous injection occurs the needle should be left behind and hyaluronidase injected.
- Intra-arterial injection: This dreaded complication usually occurs when thiopentone is in advertently injected directly from a syringe into the brachial artery, an aberrant ulnar artery in the cubital fossa, or an aberrant radial artery around the wrist; in each case the artery is mistaken for a vein. The patient usually complains of intense burning pain. This is a strong indication for stopping the injection immediately. The forearm and hand may be blanched and there may be skin blisters. Intense vasoconstriction may lead to ischemia or gangrene in the forearm, hand or fingers. Ischemia results due to (i) physical obstruction of the arteriolar lumen by crystals of thiopentone which precipitate in the relatively acidic pH and (ii) Vasospasm and thrombosis initiated by intimal damage, local release of noradrenaline and ATP from damaged red cells and platelets. Treatment involves leaving the needle in place, injecting 50 mg lignocaine (5 ml of 1% solution), a vasodilator like papaverine (10-20 ml of 0.4% solution), and performing a stellate ganglion or brachial plexus block. Intravenous heparin should be started and nonurgent surgery postponed.
- Laryngeal spasm: It is likely to occur if a painful stimulus is administered with in adequate analgesia under the effect of thiopentone, e.g. anal dilatation.
- Bronchospasm: May occur in asthmatic patients.
- Allergic reactions: Severe anaphylactic reactions may occur in 1 in 14000 to 20000 administrations.
Indications
- - For induction of anesthesia.
- - Maintenance of anesthesia for very short procedures.
- - Treatment of status epilepticus.
- - To reduce intracranial pressure.
Absolute Contraindications
- - Confirmed or suspected upper airway obstruction, e.g. epiglottitis; large oral, pharyngeal or laryngeal tumors.
- - Porphyria—barbiturates may precipitate severe cardiovascular collapse, or lower motor neurone type of paralysis in patients with acute intermittent porphyria by inducing the enzyme ALA synthetase.
- - Previous hypersensitivity to a barbiturate or sulpha drugs.
Precautions
- - Severe hepatic or renal disease: Thiopentone may be injected very slowly as the volume of distribution is large, and the protein binding is low.
- - Obstetrics: Excessive dose may lead to respiratory or cardiac depression in the fetus.
- - Outpatient anesthesia: Clear-headed recovery takes time. Slow elimination from the body may result in drowsiness for 24–36 hours. Thiopentone is therefore not recommended for brief day care procedures where the patient is likely to be discharged in a few hours.
- - Other conditions: Adrenocortical insufficiency, hypothyroidism, asthma: if alternatives like ketamine are available, thiopentone should be avoided.
Propofol (Fig. 1.3)
This molecule was invented in 1980 and has been commercially available since 1986. It has achieved great popularity because of its recovery characteristics and its antiemetic effect. In many Western countries and in better funded hospitals in India it has nearly replaced thiopentone as an induction agent. It is currently about four times more expensive than thiopentone in India.
Physical Properties
Propofol is extremely lipid soluble, and insoluble in water. The commercially available solution is a 1% milky emulsion made with soyabean oil, purified egg phosphatide, glycerol and sodium hydroxide. The pH of this solution is 6-8.5. The available preparation is a 1% (10 mg/kg) solution in a 20 ml ampoule or vial. Other presentations include 2% solution and 50 ml and 100 ml vials which are suitable for infusion. Pain on injection is a bothersome side effect and can be ameliorated by (i) IV fentanyl 50-100 μg, (ii) premixing the propofol with 1-2 ml of preservative-free lidocaine.
Pharmacology
Central Nervous System
Anesthesia is induced in 20-40 seconds after intravenous administration. This is slower than with thiopentone. Cerebral blood flow, cerebral metabolic rate, intracranial pressure and intraocular pressure are all reduced. Recovery of consciousness is rapid with minimal ‘hangover’ effect.
Cardiovascular System
Propofol reduces arterial pressure to a greater degree than thiopentone. This is mostly due to vasodilatation. However propofol does have a slight negative inotropic effect resulting in a reduction in heart rate which may contribute to fall in cardiac output. In rare cases there may be severe bradycardia and asystole. A vagolytic like atropine or glycopyrrolate must always be drawn up and kept ready for administration.
Respiratory System
Apnea is common after induction and is of longer duration than thiopentone. There is no effect on the bronchial muscle tone. Laryngeal reflexes are suppressed and laryngospasm is uncommon. The jaw is relaxed. This property is very useful for insertion of a laryngeal mask airway without using muscle relaxants.
Skeletal Muscle, Gastrointestinal System, Uterus and Placenta
Propofol has no effect on gastrointestinal motility. Incidence of postoperative nausea and vomiting is significantly low after use of propofol.
Propofol has no effect on the gravid uterine muscle tone. It crosses the placenta. Its safety on the fetus and neonate is not established. Manufacturers do not recommend its use in obstetric practice, in neonates, and during lactation.
Hepatorenal Effects
Renal function is transiently depressed but to a lower degree than thiopentone. Hepatic blood flow is reduced in proportion to drop in the arterial blood pressure, however liver function tests are not deranged even after 24 hours of propofol infusion.
Pharmacokinetics
Propofol is distributed rapidly after an intravenous dose. Blood concentration drops exponentially. It undergoes hepatic glucuronidation and 88% is excreted in the urine. Clearance is much higher than hepatic blood flow, suggesting that the drug is metabolised outside the liver as well. Unlike thiopentone there is no cumulative effect with repeated doses of propofol. Its elimination from the body is unaffected even after a continuous infusion for a few days.
Administration
In healthy unpremedicated adults where concomitant narcotic is not given, 1.5-2.5 mg/kg is adequate for anesthetic induction. The elderly are very sensitive to propofol. 1-1.5 mg/kg is usually adequate. In children 3-6 mg/kg is required. Propofol is not recommended in children less than a month of age. For sedation a dose of 1.5-4.5 mg/kg/hour is used. For total intravenous anesthesia doses between 6-10 mg/ kg/hour are used.
Adverse Effects
Cardiovascular Depression
Unless propofol is given very slowly the hypotension produced is far more than with thiopentone.
Pain on Injection
About 40% patients complain of pain on injection. The incidence is reduced if a larger vein is used. Injection of 10 mg lignocaine just before propofol or adding lignocaine to propofol reduces this incidence. Accidental extravasation or intra-arterial injection does not cause adverse reactions.
Allergic Reactions
The incidence is probably the same as with thiopentone. The incidence was high with earlier preparations (‘Diprivan’) where ‘cremophor EL’ was used as solvent and vehicle.
Indications
Induction of Anesthesia
At centers where cost is not a major consideration propofol has replaced thiopentone as the routine drug for IV induction. It is however specially indicated for day care anesthesia where recovery is quicker than with thiopentone.
Sedation During Surgery
Propofol is used for sedation during regional anesthesia and during endoscopy. This must be performed with full monitoring, with facility for ventilation available, and under supervision of an anesthesiologist.
Total Intravenous Anesthesia
Propofol is currently the best drug for this technique amongst the available intravenous anesthetics. Cumulation is significantly less than any other anesthetic.9
Sedation in ICU
Propofol is used for prolonged sedation of adult patients in the ICU. Its use in children for sedation in ICU is not recommended because a number of reports with adverse outcomes.
Absolute Contraindications
- Upper airway obstruction
- Known hypersensitivity to propofol
- Prolonged sedation in children in ICU.
Precautions
These are similar to thiopentone. Use in neonates and in obstetric anesthesia is not recommended. However, propofol is safe in porphyrias.
Ketamine Hydrochloride
Ketamine (Fig. 1.4) is a phencyclidine derivative introduced in 1965. The unique property of this drug is that, unlike other intravenous anesthetics it produces dissociative anesthesia rather than generalised depression of the CNS.
Pharmacology
Central Nervous System
After intravenous injection it produces anesthesia in 30-60 seconds. The anesthetic effect lasts 15-25 minutes. It is a potent analgesic at subanesthetic doses. Amnesia lasts well into the recovery period after consciousness is regained. Emergence is associated with restlessness, agitation, and disorientation in some patients. Vivid nightmares and hallucinations may occur up to 24 hours after the anesthetic. This emergence delirium is reduced if the patient is not stimulated in the recovery period, and if concomitant narcotics or benzodiazepines are given.
EEG changes are unlike those seen with other anesthetics. There is a predominant theta activity. Cerebral metabolic rate, cerebral blood flow, and intracranial pressure are increased. This means that ketamine is to be avoided in patients who have elevated ICP.
Cardiovascular System
Arterial pressure, heart rate and pulmonary vascular resistance are increased by 20-40%. The myocardial oxygen consumption is increased. Intrinsically ketamine is a direct myocardial depressant. The increase in blood pressure is because of its sympathetic system-stimulating action.
Respiratory System
There may be transient apnea. However after return of respiration the minute ventilation is maintained or increased. Pharyngeal and laryngeal reflexes tend to be better preserved than with other anesthetics. However all precautions must be taken to protect the airway and prevent aspiration. Tracheal intubation should not be attempted under ketamine anesthesia. Bronchodilation is an advantage, but this effect may be offset by bronchorrhea (excessive bronchial secretions).
Other Systems
- Skeletal muscle tone is increased. Ketamine cannot be used as sole anesthetic for surgery requiring muscle relaxation.
- Ketamine crosses the placenta and is therefore not ideal for obstetric anesthesia.
- Intraocular pressure increases. The eyeball is not akinetic and nystagmus may be observed. Ketamine is therefore not ideal for ocular surgery.
Pharmacokinetics
The plasma concentration falls as the drug is distributed in the body. This reduction is not as rapid as with other intravenous anesthetic agents. It is metabolised in the liver to norketamine, conjugated and excreted.
Administration
Ketamine is available as 10 mg/ml aqueous solution. The average intravenous induction dose is 2 mg/kg. Additional doses of 1-1.5 mg/kg are required every 5-10 minutes, if anesthesia is being maintained with ketamine. The intramuscular (IM) dose is 8-10 mg/kg.
Adverse Effects
- Emergence delirium and hallucinations.
- Hypertension and tachycardia. This would be harmful in patients with coronary artery disease.
- Delayed recovery.
- Increased intracranial pressure.
Indications
Patient in Shock for Emergency Surgery (e.g. Splenic/Hepatic/Thoracic Injury)
Ketamine is preferred over thiopentone or propofol. However, arterial pressure may still decrease if hypovolemia is present; volume replacement should be continued.
Pediatric Anesthesia
The drug is suitable and very useful for children undergoing short procedures like cardiac catheterization, examination under anesthesia and radiotherapy.
The Poor-risk Elderly Patient
Ketamine is preferable to other induction agents for this patient sub-group when presenting for surgery.
Difficult Locations
To provide analgesia to trauma victims for onsite debridement, fracture reduction or prior to moving. Analgesia for trapped or injured victims at the site of an accident can be provided with IM ketamine.
Treatment of Postoperative or Intractable Pain
Ketamine has been administered through subcutaneous, extradural and intrathecal routes for this purpose.
Change of Wound Dressing
Sedation and analgesia are frequently required for burns dressing in the ward. Ketamine is useful for this purpose.
Developing Countries
Ketamine is considered safer than other IV anesthetics because of absence of cardiovascular and respiratory depression. It is still extensively used in developing countries due to this safety factor especially where anesthesia sevices are rudimentary.
Absolute Contraindications
Upper airway obstruction—although the airway is better maintained than other anesthetics, airway control is not guaranteed.
- - Raised intracranial pressure.
- - Raised intraocular pressure.
Precautions
- - Cardiovascular disease: Ketamine is unsuitable for patients with ischemic heart disease and hypertension.
- - Day care anesthesia: Because of delayed recovery ketamine is not ideal in this situation.
- - Psychiatric conditions: Emergence phenomena may be confused with psychiatric illness.
Benzodiazepines
Benzodiazepines are primarily used as hypnotics and anxiolytics. The newer, shorter acting analogues are used for sedation and anesthesia.
Pharmacology
Mechanism of Action
Benzodiazepines act by binding to the benzodiazepine receptor. This receptor is part of the GABA (gamma amino butyric acid) complex on the cell membrane. Binding of the benzodiazepine to the receptor leads to influx of chloride ions into the cell leading to hyper polarisation, which makes the neurone resistant to excitation.
The benzodiazepine receptor apart from an agonist also binds inverse agonist. An example of inverse agonist binding to the same GABA site on neurones is R015-4513, which produces anxiety and cerebral excitement. Both agonist and inverse agonist are antagonised by flumazenil, a benzodiazepine antagonist.
Central Nervous System
Sedation and anesthesia: dose-dependent depression of cerebral activity occurs. Suppression of neuronal activity between the limbic system and hypothalamus modifies emotional responsiveness and behavior. Reduction in alertness and arousal reactions is seen due to depression of interaction between the limbic and reticular activating systems. As more receptors are blocked the patient progresses from a state of sedation to general anesthesia.
Amnesia: Anterograde amnesia is seen with all benzodiazepines. Retrograde amnesia is occasionally seen.
Anticonvulsant action: All benzodiazepines have an anticonvulsive action probably due to inhibition of the amygdaloid nuclei.
Anxiolysis: In smaller doses these drugs reduce anxiety. They are therefore popular as premedicants.
Muscle Relaxation
Benzodiazepines produce mild reduction in muscle tone. This is not due to effect on the neuromuscular tone but due to suppression of polysynaptic reflexes in the spinal cord. Benzodiazepines are also considered as centrally acting muscle relaxants.
Respiratory System
Benzodiazepines produce depression of ventilation. Synergistic effect is observed with narcotics. In patients with severe respiratory disease benzodiazepines can precipitate respiratory failure.
Cardiovascular System
Benzodiazepines reduce blood pressure by reducing systemic vascular resistance. In patients with hypovolemia, hypotension can be severe.
Pharmacokinetics
Benzodiazepines are non-polar and highly lipid soluble, hence well absorbed after oral administration. This makes it very convenient to administer them as premedicant drugs. Most are extensively protein-bound; only the unbound fraction can cross the blood-brain barrier or diffuse across the placenta. They are almost entirely metabolized and small fractions may be excreted unchanged. Diazepam is converted to several active metabolites (Fig. 1.5). Midazolam has a high intrinsic hepatic clearance. After intravenous injection the action of midazolam is terminated by redistribution. It undergoes extensive hepatic metabolism and the water soluble metabolites are excreted by the kidneys.
Midazolam (Fig. 1.6)
On intravenous injection, sedation or anesthesia, depending on the dose given, starts in 90 seconds, and the peak effect occurs in 2-3 minutes. Its elimination half life is two hours. It is available as 1 or 5 mg/ml solution.
Dosage
When given on its own the anesthetic dose is 50-150 micrograms/kg. Midazolam has a synergistic effect when given with narcotics or other induction agents like propofol.
The oral dose for premedication is 0.5 mg/kg. Midazolam has also been used through the nasal route (0.3 mg/kg) in children, but this route is not popular.
Diazepam (Fig. 1.7)
This commonly used benzodiazepine is insoluble in water and is solubilized in buffered propylene glycol and ethanol to a pH of 6.4-6.9. This makes it very painful for intramuscular injection and there is a high incidence of thrombophlebitis on IV administration. It is available in amber-colored ampoules containing 5 mg/ml. There is another formulation prepared in soya bean oil emulsion (‘Diazemuls’) which is non-irritant to veins and tissues. The main metabolite is the active N-desmethyldiazepam. When diazepam is used chronically in late pregnancy or labor, nordiazepam can accumulate in fetal tissues and produce the ‘floppy’ baby syndrome. The neonate is hypothermic, hypotonic and depressed.
Flumazenil
It is a benzodiazepine antagonist. Flumazenil has receptor affinity and minimal intrinsic effect. Its half life is 1 hour. It is used to diagnose benzodiazepine over dosage. It is also used to reverse the residual effect of benzodiazepines after use for sedation or anesthesia. The dose for this purpose is 0.1-1 mg. Higher doses up to 3 mg may be given, if needed, as in re-sedation.
Side Effects and Contraindications of Flumazenil
Re-sedation
Re-sedation could occur because of the short half life of the drug. Thus flumazenil may need to be repeated; patients suspected of midazolam overdose should be kept under observation till recovery is complete.13
Convulsions
In epileptic patients there is a risk of seizures, especially when benzodiazepines have been used as anticonvulsants.
Intracranial Pressure Increase
In patients with head injury the intracranial pressure may suddenly increase if flumazenil is given.
OPIOID (NARCOTIC) ANALGESICS
Opioids are conventionally looked upon as potent pain killers. These drugs depress the central nervous system, reduce the MAC of inhaled anesthetics, and in very high doses (40-60 times the usual dose) may produce complete anesthesia on their own.
Classification
Opioids can be classified as (a) naturally occurring-morphine, codeine, and papaverine; or (b) semi synthetic-buprenorphine, hydromorphone; or (c) synthetic-pethidine, fentanyl, sufentanil, alfentanil, and remifentanil.
Opiate Receptors
Opioids act on specific receptors. These receptors were discovered in 1973. These were named μ, κ, σ and δ. Since then it has been found that σ is not an opioid receptor. There are subtypes of each of these receptors (i.e. μ1, μ2, μ3 and 3k subtypes). It is suggested that is an analgesic receptor and μ2 causes respiratory depression. Morphine induced analgesia is a typical example of μ1 stimulation. Another agonist and its receptor, named nociceptin, were discovered in 1995.
Endogenous Opioid Agonists
Encephalin, β-endorphin, and dynorphin are the agonists that exist in the body for receptors δ, μ, and κ, receptors respectively.
Mechanism and Sites of Action
The opioid receptor is part of the G-protein inhibitory complex on the cell membrane. μ receptors are located in both the brain and spinal cord. The highest concentrations are found in the periaqueductal gray (brain) and substantia gelatinosa (spinal cord). μ1 and κ3 are related to supraspinal analgesia. κ receptors are found in the caudate and dorsal nuclei. δ receptors are located mainly at spinal level. Opioid receptors are also found on the nerve terminals of the afferent neurone. When an agonist binds to a receptor the following events occur:
- Inhibition of calcium channels at the presynaptic terminal of the afferent nociceptor neurone prevents calcium from entering these cells. Calcium entry in the afferent nociceptor neurones leads to release of excitatory neurotransmitters, and depolarisation.
- Opioids increase potassium efflux at the post synaptic terminal, leading to hyperpolarization. In this state a higher voltage change is required to depolarize the cell.
- Activation of central descending inhibition. This occurs in the periaqueductal grey matter.
Agonists, Antagonists, and Partial Antagonists
When a drug or an endogenous substance (a ligand) binds to a receptor and produces its full physiological effect it is called an agonist (e.g. morphine). When a ligand binds to the receptor and does not produce any physiological effect and blocks the binding of an agonist it is called an antagonist (e.g. naloxone). When a ligand binds to the receptor but increasing doses do not produce maximum physiological effect it is called a partial antagonist (e.g. buprenorphine).
Actions
Analgesia
μ receptor agonists are more effective in producing analgesia than κ receptor agonists like pentazocine.
Respiratory System
Opioids depress ventilation. The hypoxic drive is reduced, and the sensitivity to carbon dioxide 14is also reduced. Typically the respiratory rate is reduced more than the tidal volume. Opioids depress the tone of the muscles that keep the upper airway patent. As a result of this the airway is likely to get obstructed.
Cardiovascular System
If PaCO2 is maintained opioids do not have any direct effect on the cardiovascular system. The vasomotor centre is not depressed. Hypotension seen with morphine use is an indirect effect due to histamine release.
Nausea and Vomiting
All opioids cause nausea and vomiting by stimulating the chemoreceptor trigger zone.
Cough Suppression
Antitussive action is independent of analgesic effect. Some opioids like codeine have significant antitussive effect but much less analgesic activity.
Gastrointestinal Tract
Opioids reduce motility and increase the tone of the gastrointestinal tract. Morphine increases biliary pressure.
Other Effects
- - Miosis
- - Suppression of endocrine response to pain. These hormones include adrenaline, noradrenaline, cortisone, and glucagon.
- - Pruritus
- - Hallucinations
- - Dependence and tolerance
Morphine (Fig. 1.8)
Morphine has all the classic opioid effects mentioned above. It is extensively used as analgesic intraoperatively and in the postoperative period.
The IM dose for premedication is 0.15-0.3 mg/kg. An antiemetic like promethazine needs to be administered concomitantly to reduce nausea and vomiting. The normal IV analgesic dose is 0.1-0.3 mg/kg. Morphine can be used as infusion for postoperative pain relief in a dose of 10-40 μg/kg/hour, titrated to requirement.
Pethidine (Fig. 1.9)
This synthetic opioid also has atropine like effects. It has lesser effects on the biliary and renal tract than morphine. It is also shorter acting than morphine. Pethidine is metabolised to norpethidine. Norpethidine has stimulatory effects on the central nervous system. Monoamine oxidase inhibitors (MAOIs) increase the metabolism to norpethidine. As a result of this if pethidine is given to patients on MAOIs it may cause convulsions, hyperthermia, and death.
The IM dose of pethidine for premedication is 1-1.5 mg/kg, and like morphine an antiemetic agent like promethazine (0.5 mg/kg) administered concomitantly is useful. The commonly used IV dose is 0.5-1 mg/kg.
Fentanyl (Fig. 1.10)
This synthetic opioid is very lipid soluble and has a more rapid onset of action than morphine. Its duration of action is much shorter than morphine while the elimination half life is like morphine. The short effect is entirely due to redistribution. It is about 100 times more potent than morphine. The normal IV dose is 2-4 μg/kg. It has been used as the sole anesthetic in patients where cardiovascular stability is required. The dose required for this use is 40-70 μg/ kg. Fentanyl is used as a transdermal controlled release patch for use in patients with chronic pain. Fentanyl lollipops are available for transmucosal (oral) premedication in children.
One of the alarming side effects with large doses of IV fentanyl is chest wall rigidity which makes ventilation impossible unless a muscle relaxant is administered. A few patients cough after rapid IV administration.
Alfentanil
Alfentanil has a rapid onset of action, and a shorter duration of action than fentanyl. It is ten times as potent as morphine and one-fourth to one-tenth as fentanyl. Its elimination half life is 84-90 minutes, which is much lesser than fentanyl. Cumulation is much less of a problem with alfentanil and unlike fentanyl it is safer to use as continuous infusion. Most of its other effects are like fentanyl. The IV dose of alfentanil is 5-10 μg/kg, with supplemental doses of 3-5 μg/kg.
Sufentanil
Sufentanil is 10-15 times as potent as fentanyl, and has a slightly shorter duration of action. It is less likely to accumulate in the body than fentanyl. The usual dose is 0.1-0.5 μg/kg. It has recently been licensed for use in India.
Remifentanil
It is an ultra short-acting, u receptor agonist with no cumulative effect. It is given as an infusion during operation. It is metabolised by blood and tissue esterases. Remifentanil is used in a dose of 0.5-1 μg/kg as a bolus before laryngoscopy, and continued as an infusion of 0.25-0.5 μg/kg/min. Within 3-5 minutes after stopping the infusion the effect of remifentanil is terminated no matter how long the infusion has been running. It is thus well suited for outpatient use. It is not yet licensed for use in India.
Tramadol
It is a predominantly µ receptor agonist with a weak action. It is less likely to cause respiratory depression than morphine. The side effects include nausea, vomiting, dry mouth, and urinary retention. It interacts like pethidine with MAOIs.
Pentazocine
It is a σ and κ receptor agonist and has antagonist/partial agonist effect on the μ receptor. It is largely not used in the West but still commonly available and used in India. It has a ceiling analgesic effect of 60 mg in an adult. It can cause hallucinations.
Naloxone
It is a short acting opioid antagonist. Because of its short duration of action the reversal of respiratory depression induced by naloxone may be short lived. Hence patients must be monitored for some time after naloxone is used. Intense pain may occur as the analgesic effect 16of the originally given opioid is terminated. This may result in tachycardia, hypertension or even myocardial ischemia.
In conclusion, Intravenous anesthetic agents, sedatives and narcotics are an essential part of modern anesthetic practice. They have contributed tremendously to patient comfort and safety.
STATE WHETHER TRUE (T) OR FALSE (F)
- An ideal intravenous anesthetic
- Should cause rapid induction of anesthesia
- Should have cumulative effect
- Should not cause pain when injected
- Should not cause muscle relaxation
- Should not cause respiratory depression
- Regarding intravenous anesthetics
- Upper airway obstruction is an absolute contraindication for their use
- Previous known anaphylactic reaction is a relative contraindication
- All are contraindicated in porphyrias
- Are preferred over inhalation anesthetics for induction
- All can be used as continuous infusion
- Barbiturates
- Were the most commonly used intravenous anesthetics until the last 15 years
- Methyl barbiturates like methohexidone may cause excitation during induction
- All are antiepileptic
- All have very quick induction and slow recovery properties
- Have been used since 1820s
- Thiopentone sodium
- Is available as white emulsion
- Is packed in glass vials with nitrogen to prevent oxidation
- Sodium carbonate is added to keep solution alkaline at pH 10.5-10.8
- Is commonly injected in concentration of 2.5%
- Methyl paraben is added as a bacteriostatic
- Thiopentone sodium
- Produces anesthesia within 30 seconds of injection
- Has excellent analgesic property
- Is very lipid soluble
- Reduces the CMRO2
- Reduces intracranial pressure when ventilation is maintained
- Thiopentone sodium should be used very carefully in patients with
- Epilepsy
- Constrictive pericarditis
- Significant mitral stenosis
- Significant aortic stenosis
- Shock
- Thiopentone sodium
- Is a respiratory stimulant
- May cause laryngeal spasm if patient stimulated in light planes of anesthesia
- Is a uterine dilator
- Infusions lead to significant cumulation and prolonged recovery
- Un-noticed inadvertent intra-arterial injections may cause or lead to ischemia of the arm or fingers
- Propofol
- Is available as powder to be dissolved in water
- Usually causes pain on injection
- Causes hangover
- Has anti-emetic property
- Apnea is commoner than with thiopentone
- Propofol
- Ketamine
- May cause hallucinations
- Decreases intracranial pressure
- More likely to maintain respiration than other anesthetics
- Causes severe hypotension
- Less likely to cause cumulation than thiopentone
- Midazolam
- Causes sedation by chloride ion influx in the cell
- Is a short acting anesthetic
- May cause anterograde amnesia in sedative doses
- Can be used for premedication
- Is hallucinogenic
- Opiates
- Cause μ receptor stimulation that leads to respiratory depression
- Pethidine is extracted from poppy seeds
- Cause nausea and vomiting
- May increase intracranial pressure if ventilation is not controlled
- μ receptor is more effective in causing analgesia than kappa receptor
- TFTFT
- TFFTF
- TTFFF
- FTTTF
- TFTTT
- FTTTT
- FTFTT
- FTFTT
- TTFTT
- TFTFT
- TFTTF
- TFTTT